Drug release system

ABSTRACT

There is disclosed a device and method for delivery of a chemotherapeutic over a prolonged period of time to the body. In case the therapeutic has an adverse effect on the body the device can be flushed and a more suitable therapeutic substituted.

United States Patent 1191 Arlen Mar. 12, 1974 DRUG RELEASE SYSTEM3,220,960 11/1965 Wichterle 128/127 x 3,310,051 3/1967 Schulte 128/350 RX [75] Ade", Great Neck 3,313,289 4/1967 Kapral 128/1 R 73] AssigneeZHydr Med Sciences Inc" New 3,527,220 9/1970 Summers 128/260 o Delgado R3,641,237 2/1972 Gould et a1. 128/260 [22] Filed: May 17, 1973 PP N05361,153 Primary Examiner-Aldrich F. Medbery Relaed Application DataAttorney, Agent, or F irmCushman, Darby & [62] Division of Ser. No.233,685, March 10, 1972, Pat. ctishman 57 ABSTRACT [52] CL 128/260128/214 0 There is disclosed a device and method for delivery of In A6lm31/00 a chemotherapeutic over a prolonged period of time [58] Fie'ld E127 350 to the body. In case the therapeutic has an adverse efl28/l 2fect on the body the device can be flushed and a more suitabletherapeutic substituted.

[56] References Cited UNITED STATES PATENTS 9 Chums 5 Drawmg F'gms2,976,576 3/1961 Wichterle 128/214 R X DRUG RELEASE SYSTEM This is adivision, of application Ser. No. 233,685 filed Mar. 10, 1972, now U.S.Pat. No. 3,765,414.

The present invention relates to a device and method for the delivery ofchemotherapeutic agents in human or veterinary medicine, e.g. in thetreatment of humans as well as domesticated animals such as dogs, cats,horses, cattle, pigs, goats, sheep, chickens, turkeys or even wildanimals such as may be found in zoos, using a device having a shapedconfiguration, e.g. as a pouch or capsule.

The device of the present invention can be employed topically,subcutaneously or implanted at various locations in an animal or human,either above or below the integument.

The device employed in the present invention in its simplest formcomprises a hollow chamber for receipt of a medicament, a tube forintroducing medicament to the chamber, a tube for removing medicamentfrom the chamber, a relatively thick body wall for such a chamber and arelatively thin membrane for controlled release of medicament to thehuman or veterinary host.

The process and device of the present invention permits the release ofany desired medicament on a timed basis which can be as short as an houror several hours but which can be as long as days, months or even years.

The device can also be used to permit the varying of medicine. Thus thedevice permits the rotation of medicaments as desired. Alternatively inthe case of allergy or anaphylactic reaction, or if the patient is toxicto the medicine for example, the chamber can be flushed immediately toremove the adversely reacting material, e.g. if a patient is being givenpenicillin and has a reaction thereto the penicillin can be flushed outand streptomycin introduced into the chamber.

The medicament (or mixture of medicaments) can be released on a flatcurve or in any way or concentration as desired.

An additional function of the device is to overcome heretofore toxic,tissue or side-effect reactions encountered using present day methods ofadministering medicaments such as pills, injections, etc.

The devices can be fabricated from a wide variety of polymeric materialssuch as natural rubber, synthetic rubbers, e.g. cis-isoprene rubber,rubbery butadienestyrene copolymer, rubbery butadiene-acrylonitrilecopolymer, polychloroprene, butyl rubber (e.g. isobutylene-butadienecopolymer 98.5 1.5, see also U.S. Pat. No. 2,356,128),ethylene-propylene-terpolymer rubber (e.g. ethylenepropylene-norbornadiene or ethylenepropylene-cyclooctatriene,ethylene-propylenedodecatriene, etc. polyvinyl pyrrolidone, siliconepolymers, e.g. rubbery, polydimethyl siloxane such as a medical gradesilastic, polyvinyl chloride and vinyl chloride copolymers, e.g. vinylchloride-vinyl acetate copolymer (87 l3), N-methyl acrylamide polymers,N-butyl acrylamide polymers, diacetone acrylamide polymers, polyvinylalcohol, polyvinyl acetate, cellulosics, e. g. cellulose acetate,cellulose acetate-propronate, ethyl cellulose, methyl cellulose,carboxy-methyl cellulose and hydroxy ethyl cellulose, ethylene-vinylacetate copolymer, polyurethanes, e.g. toluene diisocyanate reacted withpolytetramethylene glycol or with ethylene glycol-propyleneglycol-adipate-maleate, polyimides, e.g. from methylene dianiline oroxydianiline and pyromellitic anhydride, polyamides, e.g. nylon 6,

nylon 6,6, nylon 6,11, polyacrylonitrile, polyethers, polyesters, e.g.polyethylene terephthalate, polymerized propylene glycol adipatemaleate, fluoroplastics, e.g. polytetrafluoroethylene (Teflon),tetrafluoroethylene-hexafluoropropylene copolymer, polyvinylidenefluoride, polymerized olefins, e.g. polyethylene, polypropylene,ethylene-propylene copolymer (e.g. 50:50), polyisobutylene,polybutylene, polystyrene, high impact modified polystyrene (e.g.polystyrene blended with a minor amount of rubber, polysulfones,polycarbonates such as Lexan (bisphenol A polycarbonate), polyacrylatesand methacrylates, e.g. polyethyl acrylate, polymethyl methacrylate,polybutyl methacrylate, poly 2-ethylhexyl acrylate, polyalkoxyalkylacrylates and methacrylates, e.g. polymers, methoxyethyl acrylate,ethoxyethyl acrylate, butoxyethyl acrylate, methoxypropyl acrylate,methoxyethyl ethoxyethyl methacrylate and methoxypropyl methacrylate,hydroxyethoxyethyl methacrylate, hydroxypropoxypropyl methacrylate,hydroxyethoxyethyl acrylate.

The preferred polymers are hydrophilic polymers made from a monomerwhich is a hydroxy lower alkyl acrylate or methacrylate, or hydroxylower alkoxy lower alkyl acrylate or methacrylate, e.g., 2- hydroxyethylacrylate, 2-hydroxyethyl methacrylate, diethylene glycol monoacrylate,diethylene glycol monomethacrylate, Z-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl acrylate, 3-hydropropylmethacrylate and dipropylene glycol monomethacrylate. The polymersproduced from slurries of monomers are organic solvent soluble, e.g.alcohol soluble, but water insoluble. They can be preparsdiqs wtm s a sbwt m n h srdib Pat. N

3,6l8,2l3 e.g. example 364 1, or Chromacek U.S. Pat.

The hydroxyalkyl acrylate or methacrylate less preferably can also bereplaced by vinyl pyrrolidone, acrylamide, methacrylamide, N-propylacrylamide, N- isopropyl methacrylamide, N-methylacrylamide,N-methylmethacrylamide, N-methylol acrylamide and N-methylolmethacrylamide, N-2-hydroxyethyl acrylamide, N-Z-hydroxyethylmethacrylamide. However, these monomers usually form water solublehomopolymers and hence they require the presence of a crosslinking agentor copolymerization with a sufficient amount of the hydroxyalkylacrylates and methacrylates to render the copolymers water insoluble.

Other ethylenically unsaturated monomers can be used in conjunction withthe above monomers or copolymers to constitute hydrophilic polymericmatrixes suitable for the entrapment of enzymes. They include neutralmonomers such as acrylonitrile, methacrylonitrile, vinyl acetate, alkylacrylates and methacrylates, alkoxyalkyl acrylates and methacrylates.

Examples of alkyl acrylates and methacrylates include methyl acrylate,ethyl acrylate, butyl acrylate, 2- ethylhexyl acrylate, methylmethacrylate and butyl methacrylates. Examples of suitable alkoxyalkylacrylates and methacrylates are methoxyethyl acrylate, methoxyethylmethacrylate, ethoxyethyl acrylate ethoxyethyl methacrylate,propoxyethyl acrylate, butoxyethyl methacrylate, methoxypropyl acrylate,ethoxypropyl methacrylate. These comonomers when used in an amountpreferably not higher than 50 percent (and usually between 0.5 and 20%)of the monomeric mixture contribute to improve the mechanical propertiesmethacrylate,

of the gel. They should not be used in an amount to impair thehydrophilic nature of the polymer. Other vinyl monomers bearingionizable functional groups can be copolymerized with the hydroxyalkylacrylates or methacrylates to constitute ionogenic matrixes which can beuseful when a basic or acidic environment is required for the stabilityor the optimum activity of enzymes. They include acidic type monomerssuch as acrylic acid, methacrylic acid, maleic acid, fumaric acid,itaconic acid, aconitic acid, cinnamic acid, crotonic acid, carboxylicacid, propiolic acid, citraconic acid, vinyl sulfonic acid,p-vinylbenzenesulfonic acid, partial esters such as mono-2-hydroxyethylitaconate, mono-2-hydroxypropyl citraconate, mono-2- hydroxyethylmaleate, mono-2-hydroxypropyl fumarate, monomethyl itaconate, monoethylitaconate, monomethyl cellosolve itaconate (Methyl Cellosolve is themonoethyl ether of diethylene glycol), monomethyl Cellosolve maleate,mono-2-hydroxyethyl aconitate.

They also include basic type monomers such as aminoethyl methacrylate,dimethyl aminoethyl methacrylate, monomethyl-aminoethyl methacrylate,tbutylaminoethyl methacrylate, p-amino-styrene, oaminostyrene,2-amino-4-vinyltoluene, diethylaminoethyl acrylate, dimethylaminoethylacrylate, tbutylaminoethyl acrylate, piperidinoethyl acrylate,piperidinoethyl methacrylate, morpholinoethyl acrylate, morpholinoethylmethacrylate, 2-vinyl pyridine, 3-vinyl pyridine, 4-vinyl pyridine,2-ethy1-5-vinyl pyridine, dimethylaminopropyl acrylate, dimethylaminopropyl methacrylate, dipropylaminoethyl acrylate, dimethylaminoethylvinyl ether, dimethylaminoethyl vinyl sulfide, diethylaminoethyl vinylether, aminoethyl vinyl ether, 2-pyrrolidinoethyl methacrylate, 3-(dimethylaminoethyl)-hydroxypropyl acrylate, 3-(dimethylaminoethyl)-2-hydroxypropyl methacrylate, 2-aminoethylacrylate, 2-aminoethyl methacrylate. The alkylaminoethyl acrylates andmethacrylates are preferred in this group. These ionogenic monomersshould not be used in sufficient amounts to render the hydroxyalkylacrylates or methacrylates water soluble. Multipolymers prepared from amixture of 3,4 or more of the above monomers can be used. These monomersare usually used in an amount of 0.1 20%, preferably 1 to 15% of thetotal monomers.

When it is necessary to render the membrane insoluble in organicsolvents, this can be done by sparingly cross-linking the entrappingpolymer. Preferably, the cross-linking agent is added in an amount of 1to most preferably, not over 2.0% or 2.5%, although from 0.05 to or evenof cross-linking agents can be used. Cross-linking renders the otherwiseorganic solvent soluble or watersoluble polymers insoluble, although itdoes not impair the hydrophilic properties.

Typical examples of cross-linking agents include ethylene glycoldiacrylate, ethylene glycol dimethacrylate, 1,4-butylene dimethacrylate,diethylene glycol dimethacrylate, propylene glycol dimethacrylate,diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate,diethylene glycol diacrylate, dipropylene glycol diacrylate, divinylbenzene, divinyl toluene, diallyl tartrate, allyl pyruvate, allylmalate, divinyl tartrate, triallyl melamine, N,N'-methylenebisacrylamide, diallyl maleate, divinyl ether, diallyl monoethyleneglycol citrate, ethylene glycol vinyl allyl citrate, allyl vinylmaleate, diallyl itaconate, ethylene glycol diester of itaconic acid,divinyl sulfone, hexahydro-l, 3, S-triacryltriazine,

triallyl phosphite, diallyl esther of benzene phosphonic acid, polyesterof maleic anhydride with triethylene glycol, diallyl aconitrate, divinylcitraconate, diallyl fumarate, ammonium dichromate.

Especially useful are water insoluble hydrophilic polymers ofhydroxyalkyl acrylates and methacrylates having 2 to 4 carbon atoms inthe alkyl group particularly hydroxyethyl methacrylate (HEMA), althoughthere also can be used polymers of hydroxypropyl methacrylate,hydroxybutyl methacrylate, hydroxyethyl acrylate or hydroxy propylacrylate. The polymers of this preferred group can be homopolymers ormore preferably are copolymers containing a small amount, e.g. 0.05 to20% preferably 0.1 to 2% of a cross-linking agent to give a sparinglycross-linked polymer. Examples of such cross-linking agents are ethylenedimethacrylate, propylene dimethacrylate, butylene dimethacrylate,ethylene diacrylate, butylene diacrylate, diethylene glycol diacrylate,diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate,triethylene glycol diacrylate, triethylene glycol dimethacrylate,tartaric acid dimethacrylate, methylene bis acrylamide, triallylcyanurate or other cross-linking agents such as disclosed in WichterleU.S. Pat. No. 3,220,960 or Shepherd U.S. Pat. No. 3,575,123 or ShepherdU.S. Pat. No. 3,577,512 or Shepherd U.S. Pat. No. 3,618,213 can be used.The entire disclosure of the Wichterle patent and the three Shepherdpatents is hereby incorporated by reference. The hydroxyalkyl acrylate(with or without the cross-linking agent can be copolymerized with aminor amount, e.g. 0.1 to 49%, usually not over 20%, of anothermonoethylenically unsaturated monomer, e.g. methyl methacrylate, vinylpyrrolidone, vinyl acetate, methoxyethyl methacrylate, ethoxyethylmethacrylate, butyl acrylate, etc. The hydrophilic polymer such as aHEMA polymer can be prepared in anhydrous form, e.g. as disclosed inShep herd US Pat. No. 3,618,213 or as a hydrogel as' shown in WichterleU.S. Pat. No. 3,220,960.

The device employed in the present invention can be fabricated byutilizing conventional procedures such as injection molding, filmcasting, ultrasonic welding, heat sealing, cement bonding, etc. and canbe prepared as a single sided membrane, a double sided membrane or atotal (i.e. overall) membrane device. The devices can be rigid, semirigid or flexible.

As medicaments there can be employed compounds such as procainepenicillin, 5-fluorouracil, adrenaline (epinephrine) steroids and otherhormones such as testosterone, estradiol, diethyl stilbesterol, amixture of ethynylestradiol and mestranol, androsterone, norethandrolone(Nilevar), estrone, stilbesterol, progesterone, ll-dehydroprogesterone,desoxycorticosterone, hydrocortisone acetate, corticosterone, cortisone,9-a1pha-fluorohydrocortisone, insulin, lincomycin hydrochloride,penicillin, streptomycin, phenoxymethyl penicillin, chloramphenicol,sulfanilamide, sulfaguanidine, sulfathiazole, tetracycline,clorotetracycline, hydroxytetracycline, bacitracin, neomycin, polymyxin,gramicidin, erythromycin, sulfacetamide, sulfamethizole, thyroxinsulfisoxazole, antivirals such as idoxuridine, nitrofurazone, sodiumpropionate, anti allergenics such as antazoline, methapyrilene,chlorpheniramine, pyrilamine and prophenpyridamine, anti inflammatoriessuch as dexamethasone, dexamethasone 21- phosphate, fluocinolone,prednisolone, prednisolone acetate and prednisolone 21-phosphate,decongestants such as phenylephrine, naphazoline and tetrahydrazoline,pilocarpine, diisopropyl fluorophosphate, cyclopentolate, homatropine,hydroxyamphetamine, sedatives and hypnotics such as phenobarbital,pentabarbital sodium, butabarbital, amobarbital, secobarbital sodium,codeine, bromoisovatum, sodium and phenobarbital, pentaerythritol,tetranitrate, nitroglycerine, digitoxin, digitalis, atabrine, heparin,hydroxystilbamide, benadryl dl-amphetamine sulfate, dextro amphetaminesulfate, vitamins, e.g. Vitamin B Vitamin B Vitamin E, Vitamin K,Vitamin C (ascorbic acid), tranquilizers, e.g. reserpine, chlorpromazinehydrochloride, alkaloids, e.g. belladonna, atropine sulfate, hyoscinehydrobromide, chlorpheniramine maleate, quinidine salts, theopyllinesalts, ephedrine salts, pyrilamine maleate, enzymes, e.g. pepsin,trypsin, alphaamylase, phosphatases, glyoxalase, cytochrome oxidase,d-amino acid oxidase, l-amino acid oxidase, hyaluronidase.

When the polymer employed for the device to control the flow ofmedicament is made of a polymer which has a tissue reaction e.g.silicone, polyvinyl alcohol, Teflon and most of the other polymers whichare tissue irritating, it is preferred to eliminate the tissueirritation by employing a polymer of a hydroxyalkyl acrylate ormethacrylate, e.g. a HEMA polymer, as a thin biocompatible overallcoating.

There are a number of different designs for the devices used in thepresent invention. Several of these are shown in the accompanyingdrawings wherein FIG. 1 is a vertical elevation of one type of deviceaccording to the invention;

FIG. 2 is a vertical elevation of an alternative device;

FIG. 3 is a view of a bag device according to the invention having anon-toxic coating;

FIG. 4 is a vertical elevation of a device similar to that of FIG. 1 buthaving a biologically acceptable coating; and

FIG. 5 is a vertical elevation of a device similar to that of FIG. 2 buthaving a biologically acceptable coat- Referring more specifically toFIG. 1, there is disclosed an implantable device in the shape of half ofa capsule having a relatively thick body wall 4 on the body of thedevice, e.g. a hydrophilic hydrogel copolymer of hydroxyethylmethacrylate with 0.2% of ethylene dimethacrylate and having arelatively thin membrane end wall 6 of the same material. The wall 4 hastwo straight portions 8 and 10 joined by an arcuate portion 12.

The wall 4 and membrane end wall 6 enclose a hollow chamber 14 whichcanbe filled with a drug through entry channel or tube 16. In the eventit is necessary to flush out and replace the drug, this can beaccomplished for example by passing a cleaning fluid or a different drugthrough channel or tube 16 into chamber 14 and forcing the old drug outthrough exit channel or tube 18. Tubes 16 and 18 can be closed off byany suitable valve outside the body. Tubes 16 and 18 can be made of thesame material as the rest of the device or any other suitable material,e.g. Teflon, Silastic, polyvinyl chloride, rubber, etc. The membrane 6can be of the same material as the wall 4 or it can be made of adifferent material.

In the form of the invention as shown in FIG. 2, the implant device 20is basically in the form of an O ring having a relatively thick frontwall 22 and a back wall (not shown). The side walls 28 and 30 each areof a relatively thin membrane. There are also provided fluid entrychannel 34 and fluid exit channel 36 into drug receiving chamber 38. Theimplant device, for example, can be essentially in the form of a ringsimilar to that in FIG. 2 of Kapral U.S. Pat. No. 3,313,289.

In the embodiment shown in FIG. 2 the two membrane sides can be of thesame or different thickness. If they are of the same thickness and madeof the same material, e.g. hydroxyethyl methacrylate copolymer, then therate of diffusing materials out of the chamber will be the same.However, the rates can be varied by changing the relative thickness ofthe two membranes, e.g. 1.1:1, 1.5:1, 2:1, 4:1 or 10:1 so that the ratesofdiffusion will be different. This can be important when it is desiredto introduce the same medicament simultaneously to different bodyorgans.

The embodiment shown in FIG. 3 is in the form of a bag 40 having asingle body wall 42 of polytetrafluoroethylene surrounding central drugreceiving cavity 44 and a non toxic extremely thin external membrane 46of a hydrophilic polymer of hydroxyethyl methacrylate with 0.1% ethylenedimethacrylate as a crosslinking agent. There are also provided fluidentry channel 48 and fluid exit channel 50.

The device of FIG. 4 is similar to that of FIG. 1 except that the bodywall 4 and the membrane 6 are made of a biologically toxic material,e.g. Silastic (rubbery polydimethyl siloxane) and there is an overallvery thin coating 52 of biocompatible material such as HEMA polymer forboth the body wall and the membrane. The membrane and body wall can beof different materials, e.g. the body wall can bepolytetrafluoroethylene and the membrane Silastic.

The device of FIG. 5 is similar to that of FIG. 2 except that the wallsand membranes are made of a toxic material, e.g. Silastic, and the wallsand membranes have an overall very thin coating 54 of biocompatiblematerial such as a copolymer of HEMA with 0.2% of diethylene glycoldimethacrylate. Different rates of diffusion of the medicament throughmembranes 28 and 30 can be provided by making them of differentthicknesses or by making them of different materials which can have thesame or different thicknesses. Thus membrane 28 can be made ofpolymethyl methacrylate and membrane 30 of polyethylene.

The body wall or walls of the device are relatively thick e.g. at least2 mm. to provide sufficient rigidity. The body wall can be as thick as 7mm. The permeable membrane can be from 0.1 to 2 mm. thick but usually isnot over 1 mm. and preferably is 0.2 to 0.5 mm. It should not be overone-half the thickness of the body wall. The body wall can be reinforcedif desired, e.g. with Dacron (polyethylene terephthalate) fibers orother fibers either medially or externally.

When a coating biologically compatible material is employed over a morebiologically toxic material, the outer material should be very thin,e.g. 0.01 to 0.1 micron. In the total device the inner membrane isemployed to control the flow of medicament and the outer coating issolely for the purpose of preventing tissue reaction and shouldtherefore be as thin as possible so as not to interfere with such flow.

According to the present invention there can be filled into the innercavities in the devices of the drawings a medicament, such as forexample any of those specified above, or mixture of medicaments. Themedicaments can be in liquid or solid form. They also can be introducedinto the cavity in the form of a solution or suspension in water orother biologically acceptable liquid.

The device of the invention can be implanted subcutaneously,intramuscularly, interperitoneally or adjacent to any body organ or byany other conventional manner of implantation.

The device can be used to deliver medically active ingredients (1) to aspecific area of the body, e.g. an organ such as the liver, gallbladder, stomach wall, or a lung, placed between two organs, e.g.between the pancreas and the duct leading into the intestines; (2)placed adjacent to an inoperative mass, e.g. a tumor such as aSchwanoma, (3) placed within a functioning organ system to releaseactive ingredients to stimulate or reduce activity of the system, e.g.an implant directly into the peritoneum or into the stomach or theuterus.

As previously stated the device having a hollow, fillable chamber withingress and egress through small hollow tubes can be formed by anyconventional method. The hollow tubes at the time of implant can bebrought out through the skin. The entry and exit tubes can be removed atany time if desired by gentle manipulation.

The present invention is especially effective as a method of delivery ofantitumor compounds in high concentrations in the area of tumor growth.The implantable device of the invention containing the antitumor agentis placed against the tumor at the time of surgery. Because of its highdegree of biologic acceptability (see Levowitz, Trans. Amer. Soc. forArtificial lnternal Organs l4,82(l968) Hydron (a commercially availablecopolymer of 100 parts of 2-hydroxyethyl methacrylate with about 0.2parts of ethylene glycol dimethacrylate) is particularly suitable as setforth supra for forming the walls and membranes of the devices since itevokes little or no fibroblastic reaction at implantation sites.

The use of the device of the invention permits flexibility inadministering chemotherapeutic agents. Thus a drug can be discontinuedat the first sign of toxity and if the drug is ineffective, it can bereadily changed.

Using 5-fluorouracil (S-FU) and the device of FIG. 2 with Hydron as thematerial of the body walls and membranes. The device was an O-ring withtwo membranes. The S-FU was employed as a solution of 50 mg/ml. inwater. It was found that within 30 minutes 20 mgs. of 5-FU were absorbedin each gram of Hydron with a gradual incease to 30 mg/gm. of Hydron in90 minutes. i

Elution of S-FU from Hydron pledgets soaked in 0.5% S-FU for '5 days wasstudied in 0.1 molar phosphate buffer and human plasma. This pattern ofrelease was constant over the first 4 days and gradually tapered offover an interval of 120 hours.

In vivo studies in rabbits showed a similar rate of release occurredwith 65% of the S-FU entering the tissues and body fluids in the first48 hours.

The use of individual pellets of Hydron saturated with S-FU andimplanted into the peritoneal cavity of CF white mice was found to offerprotection against the growth of Ehrlichs ascites tumor cells. Five daysafter challenging implanted mice with Ehrlichs ascites tumor cells,21/22 mice were alive with the Hydron treatment versus 18/22 animalshaving Hydron with just water. On the 21st day, 17/22 animals receivingthe Hydron plus chemotherapeutic agent were alive versus 4/22 havingreceived control Hydron plus water pledgets. Thus it appeared that theHydron plus chemotherapeutic agent offered significant protection in themice.

However, polymer saturated with antitumor drugs cannot deliver effectiveserum or tissue levels. The implantable device of the invention, e.g. anO-ring of the type described using various membrane thicknesses. In vivostudies revealed fairly predictable straight line curves for release ofthe anti-tumor agent 5-F U with a window size of 1 cm. in diameter and0.15 mm membrane thickness, 1 mg of S-FU was eluted from the chamber perhour. A 1 mm. thick membrane window allowed 0.5 mg of 5-FU to be elutedper hour.

Studies employing this device implanted into the peritoneal cavity ofdogs indicated that a rapid uptake of S-FU into surrounding tissuesoccurred. The uptake appeared selective in that high concentrations ofagents reached those tissues in contact with the reservoir and rapidlytapered off at more distant sites. Even those tissues with knownpredilection for the agent appeared spared.

What is claimed is:

1. A method of introducing a plurality of medicaments into an animalbody which includes selecting an area of the body to be treated,implanting into the living tissues of the body a body implant device fordelivery of a medicament over a long period of time comprising a chamberadapted to receive a medicament, wall means sufficiently thick to beresistant to fluid flow therethrough partially surrounding said chamber,relatively thin fluid permeable membrane means engaging said wall meansand completing the surrounding of said chamber, said membrane meansbeing adapted to permit transport of fluids between the body and saidchamber, said membrane means being not over one-half the thickness ofsaid wall means, said wall means and said membrane means being made of awater insoluble hydrophilic non-toxic polymer of a member of the groupconsisting of hydroxy lower alkyl acrylates, hydroxy lower alkylmethacrylates, hydroxy lower alkoxy lower alkyl acrylates, hydroxy loweralkoxy lower alkyl methacrylates, vinyl pyrrolidone, acrylamide,methacrylamide, N-lower alkyl acrylamide, N-lower alkyl methacrylamideN-hydroxy lower alkyl acrylamide and N- hydroxy lower alkylmethacrylamide first conduit means for feeding medicament to saidchamber and second conduit means for rapid removal of medicament fromsaid chamber, introducing into the chamber of the device a firstmedicament, allowing the device to remain within the body whilepermitting said first medicament to pass through said membrane meansinto the animal body, passing a second medicament through said firstconduit means into said chamber after said device is implanted in thebody, removing the first medicament through said second conduit meansand permitting said second medicament to pass through said membranemeans into the animal body.

2. A method of introducing a plurality of medicaments into an animalbody which includes selecting an area of the body to be treated,implanting into the living tissues of the body a body implant device fordelivery of a medicament over a long period of time comprising a chamberadopted to receive a medicament, wall means sufficiently thick to beresistant to fluid flow therethrough at least partially surrounding saidchamber, relatively thin fluid permeable membrane means engaging saidwall means and either l completing the surrounding of said chamber, or(2) completely surrounding both said chamber and said wall means, saidmembrane means being adapted to permit transport of fluids between thebody and said chamber, said membranemeans being not over one-half thethickness of said wall means, said wall means and said membrane meansbeing made of a biologically incompatible material and an extremely thincoating of a water insoluble hydrophilic non-toxic, biocompatiblepolymer of a member of the group consisting of hydroxy lower alkylacrylates, hydroxy lower alkyl methacrylates, hydroxy lower alkoxy loweralkyl acrylates, hydroxy lower alkoxy lower alkyl methacrylates, vinylpyrrolidone, acrylamide, methacrylamide, N-lower alkyl acrylamide, N-lower alkyl methacrylamide, N-hydroxy lower alkyl acrylamide andN-hydroxy lower alkyl methacrylamide surrounding all externally exposedportions of said wall means and said membrane means, said coating beingsufficiently thin that it does not interfere with fluid transportthrough said membrane means, a first conduit means for feedingmedicament to said chamber and a second conduit for rapid removal ofmedicament from said chamber, introducing into the chamber of the devicea first medicament, allowing the device to remain within the body whilepermitting said first medicament to pass through said membrane meansinto the animal body, passing a second medicament through said firstconduit means into said chamber after the device is implanted in thebody, removing the first medicament through said second conduit meansand permitting said second medicament to pass through said membranemeans into the animal body.

3. A method according to claim 2 including the step of introducing saidfirst medicament into said chamber after the device is implanted in theanimal body.

4. A method according to claim 3 including the step of determining ifsaid first medicament is compatible with said tissues, upondetermination that a change of medicament is desirable because theanimal body exhibits a toxic reaction to the first medicament promptlyreplacing said first medicament by a second medicament which does nothave said toxic effects.

5. A method of introducing a plurality of mediaments into an animal bodywhich includes selecting an area of I the body to be treated, implantinginto the living tissues of the body a body implant device for deliveryofa medicament over a long period of time comprising a chamber adaptedto receive a medicament, wall means sufficiently thick to be resistantto fluid flow therethrough partially surrounding said chamber,relatively thin fluid permeable membrane means engaging said wall meansand completing the surrounding of said chamber, said membrane meansbeing adapted to permit transport of fluids between the body and saidchamber, said membrane means not being over one-half the thickness ofsaid wall means, said wall means and said membrane means being made of awater insoluble hydrophilic non-toxic biocompatible polymer of a hydroxylower alkyl acrylate or methacrylate, first conduit means for feedingmedicament to said chamber and second conduit means for rapid removal ofmedicament from said chamber, introducing into the cham- Y with saidtissues, upon determination that a change of 1 her of the device a firstmedicament, allowing the device to remain within the body whilepermitting said first medicament to pass through said membrane meansinto the animal body, passing a second medicament through said firstconduit means into said chamber after said device is implanted in thebody, removing the first medicament through said second conduit meansand permitting said second medicament to pass through said membranemeans into the animal body.

6. A method according to claim 5 including the step of determining ifsaid first medicament causes undesirabe side effects, upon determinationthat the first medicament does cause undesirable side effects replacingsaid first medicament by a said medicament which does not have said sideeffects.

7. A method of introducing a plurality of medicaments into an animalbody which includes selecting an area of the body to be treated,implanting into the living tissues of the body a body implant device fordelivery of a medicament over a long period of time comprising a chamberadopted to receive a medicament, wall means sufficiently thick to beresistant to fluid flow therethrough at least partially surrounding saidchamber, relatively thin fluid permeable membrane means engaging saidwall means and at least completing the surrounding of said chamber, saidmembrane means being adapted to permit transport of fluids between thebody and said chamber, said membrane means being not over one-half thethickness of said wall means, said wall means and said membrane meansbeing made of a biologically incompatible material and an extremely thincoating of a water insoluble hydrophilic non-toxic, biocompatiblepolymer of a hydroxy lower alkyl acrylate or methacrylate surroundingall externally exposed portions of said wall means and said membranemeans, said coating being sufficiently thin that it does not interferewith fluid transport through said membrane means, a first conduit meansfor feeding medicament to said chamber and a second conduit means forrapid removal of medicament from said chamber, introducing into thechamber of the device a first medicament, allowing the device to remainwithin the body while permitting said first medicament to pass throughsaid membrane means into the animal body, passing a second medicamentthrough said first conduit means into said chamber after the device isimplanted in the body, removing the first medicament through said secondconduit means and permitting said second medicament to pass through saidmembrane means into the animal body. I

8. A method according to claim 7 including the step of introducing saidfirst medicament into said chamber after the device is implanted in theanimal body.

9. A method according to claim 8 including the step of determining ifsaid first medicament is compatible ment which does not have said toxiceffects.

1. A method of introducing a plurality of medicaments into an animalbody which includes selecting an area of the body to be treated,implanting into the living tissues of the body a body implant device fordelivery of a medicament over a long period of time comprising a chamberadapted to receive a medicament, wall means sufficiently thick to beresistant to fluid flow therethrough partially surrounding said chamber,relatively thin fluid permeable membrane means engaging said wall meansand completing the surrounding of said chamber, said membrane meansbeing adapted to permit transport of fluids between the body and saidchamber, said membrane means being not over one-half the thickness ofsaid wall means, said wall means and said membrane means being made of awater insoluble hydrophilic non-toxic polymer of a member of the groupconsisting of hydroxy lower alkyl acrylates, hydroxy lower alkylmethacrylates, hydroxy lower alkoxy lower alkyl acrylates, hydroxy loweralkoxy lower alkyl methacrylates, vinyl pyrrolidone, acrylamide,methacrylamide, Nlower alkyl acrylamide, N-lower alkyl methacrylamideN-hydroxy lower alkyl acrylamide and N-hydroxy lower alkylmethacrylamide first conduit means for feeding medicament to saidchamber and second conduit means for rapid removal of medicament fromsaid chamber, introducing into the chamber of the device a firstmedicament, allowing the device to remain within the body whilepermitting said first medicament to pass through said membrane meansinto the animal body, passing a second medicament through said firstconduit means into said chamber after said device is implanted in thebody, removing the first medicament through said second conduit meansand permitting said second medicament to pass through said membranemeans into the animal body.
 2. A method of introducing a plurality ofmedicaments into an animal body which includes selecting an area of thebody to be treated, implanting into the living tissues of the body abody implant device for delivery of a medicament over a long period oftime comprising a chamber adopted to receive a medicament, wall meanssufficiently thick to be resistant to fluid flow therethrough at leastpartially surrounding said chamber, relatively thin fluid permeablemembrane means engaging said wall means and either (1) completing thesurrounding of said chamber, or (2) completely surrounding both saidchamber and said wall means, said membrane means being adapted to permittransport of fluids between the body and said chamber, said membranemeans being not over one-half the thickness of said wall means, saidwall means and said membrane means being made of a biologicallyincompatible material and an extremely thin coating of a water insolublehydrophilic non-toxic, biocompatible polymer of a member of the groupconsisting of hydroxy lower alkyl acrylates, hydroxy lower alkylmethacrylates, hydroxy lower alkoxy lower alkyl acrylates, hydroxy loweralkoxy lower alkyl methacrylates, vinyl pyrrolidone, acrylamide,methacrylamide, N-lower alkyl acrylamide, N-lower alkyl methacrylamide,N-hydroxy lower alkyl acrylamide and N-hydroxy lower alkylmethacrylamide surrounding all externally exposed portions of said wallmeans and said membrane means, said coating being sufficiently thin thatit does not interfere with fluid transport through said membrane means,a first conduit means for feeding medicament to said chamber and asecond conduit for rapid removal of medicament from said chamber,introducing into the chamber of the device a first medicament, allowingthe device to remain within the body while permitting said firstmedicament to pass through said membrane means into the animal body,passing a second medicament through said first conduit means into saidchamber after the device is implanted in the body, removing the firstmedicament through said second conduit means and permitting said secondmedicament to pass through said membrane means into the animal body. 3.A method according to claim 2 including the step of introducing saidfirst medicament into said chamber after the device is implanted in theanimal body.
 4. A method according to claim 3 including the step ofdetermining if said first medicament is compatible with said tissues,upon determination that a change of medicament is desirable because theanimal body exhibits a toxic reaction to the first medicament promptlyreplacing said first medicament by a second medicament which does nothave said toxic effects.
 5. A method of introducing a plurality ofmediaments into an animal body which includes selecting an area of thebody to be treated, implanting into the living tissues of the body abody implant device for delivery of a medicament over a long period oftime comprising a chamber adapted to receive a medicament, wall meanssufficiently thick to be resistant to fluid flow therethrough partiallysurrounding said chamber, relatively thin fluid permeable membrane meansengaging said wall means and completing the surroundiNg of said chamber,said membrane means being adapted to permit transport of fluids betweenthe body and said chamber, said membrane means not being over one-halfthe thickness of said wall means, said wall means and said membranemeans being made of a water insoluble hydrophilic non-toxicbiocompatible polymer of a hydroxy lower alkyl acrylate or methacrylate,first conduit means for feeding medicament to said chamber and secondconduit means for rapid removal of medicament from said chamber,introducing into the chamber of the device a first medicament, allowingthe device to remain within the body while permitting said firstmedicament to pass through said membrane means into the animal body,passing a second medicament through said first conduit means into saidchamber after said device is implanted in the body, removing the firstmedicament through said second conduit means and permitting said secondmedicament to pass through said membrane means into the animal body. 6.A method according to claim 5 including the step of determining if saidfirst medicament causes undesirab e side effects, upon determinationthat the first medicament does cause undesirable side effects replacingsaid first medicament by a said medicament which does not have said sideeffects.
 7. A method of introducing a plurality of medicaments into ananimal body which includes selecting an area of the body to be treated,implanting into the living tissues of the body a body implant device fordelivery of a medicament over a long period of time comprising a chamberadopted to receive a medicament, wall means sufficiently thick to beresistant to fluid flow therethrough at least partially surrounding saidchamber, relatively thin fluid permeable membrane means engaging saidwall means and at least completing the surrounding of said chamber, saidmembrane means being adapted to permit transport of fluids between thebody and said chamber, said membrane means being not over one-half thethickness of said wall means, said wall means and said membrane meansbeing made of a biologically incompatible material and an extremely thincoating of a water insoluble hydrophilic non-toxic, biocompatiblepolymer of a hydroxy lower alkyl acrylate or methacrylate surroundingall externally exposed portions of said wall means and said membranemeans, said coating being sufficiently thin that it does not interferewith fluid transport through said membrane means, a first conduit meansfor feeding medicament to said chamber and a second conduit means forrapid removal of medicament from said chamber, introducing into thechamber of the device a first medicament, allowing the device to remainwithin the body while permitting said first medicament to pass throughsaid membrane means into the animal body, passing a second medicamentthrough said first conduit means into said chamber after the device isimplanted in the body, removing the first medicament through said secondconduit means and permitting said second medicament to pass through saidmembrane means into the animal body.
 8. A method according to claim 7including the step of introducing said first medicament into saidchamber after the device is implanted in the animal body.
 9. A methodaccording to claim 8 including the step of determining if said firstmedicament is compatible with said tissues, upon determination that achange of medicament is desirable because the animal body exhibits atoxic reaction to the first medicament promptly replacing said firstmedicament by a second medicament which does not have said toxiceffects.